Dendritic cells (DCs) are essential antigen presenting cells (APC), which play a crucial role in the induction of specific immune response against pathogens. Immature DCs, localized in peripheral mucosal tissues throughout the body, are sentinels that monitor for the presence of pathogens. After detecting and internalizing a pathogen, DCs migrate from the site of infection to draining lymphoid organs. During this migration, DCs undergo a deep maturation that leads, among other things, to the processing of antigens from pathogen and their presentation by membrane major histocompatibility complex (MHC). Once in lymph nodes, DCs enable the selection of rare circulating antigen-specific lymphocytes and, subsequently, lymphocyte expansion and differentiation (for review, see Banchereau et al., 2000).
It clearly appears that recognition of pathogens by DCs is one of the crucial steps in the induction of protective immunity. DCs express a repertoire of receptors including Toll-like receptors and C-type lectins. C-type lectins recognize specific carbohydrate moieties that are present on the cell walls of pathogens. The binding of a pathogen by C -type lectin-carbohydrate interaction generally leads to the internalization of the pathogen.
Among C-type lectins, one may note DC-SIGN (DC-specific intercellular adhesion molecule 3 [ICAM-3]-grabbing nonintegrin), which is highly expressed at the surface of DCs. DC-SIGN is a type II membrane protein with a short amino-terminal cytoplasmic tail, a neck region and a single C-terminus carbohydrate recognition domain (CRD). The extracellular CRD is a tetramer stabilized by an alpha-helical stalk, which specifically recognizes glycosylated proteins and ligands bearing high-mannose oligosaccharides. In this respect, DC-SIGN was shown to bind the HIV-1 envelope glycoprotein gp120 that displays several high-mannose N-glycan structures, as well as to the mannose-capped cell wall component of Mycobacterium tuberculosis ManLAM (lipoarabinomannan). High binding affinity of Lewis-group antigens containing fucose residues in different anomeric linkages for DC-SIGN was also observed. Finally, it was shown that the interaction of DC -SIGN with high-mannose moieties present on glycoproteins is multivalent and calcium -dependent (Feinberg, et al., 2001; Mitchell, et al., 2001). (For review, see Kooyk and Geijtenbeek, Nat Rev Immunol., 2003, 3, 697-709).
DC-SIGN binds to a broad range of pathogens including viruses, bacteria, fungi and parasites (Kooyk and Geijtenbeek, supra). Several studies showed that some pathogens subvert DC-SIGN functions in order to escape immune surveillance, promote their dissemination and/or modulate the immune response. Such mechanisms are observed for distinct viruses such as Ebola virus (Alvarez et al., 2002), avian H5N1 influenza virus (Wang, et al., 2008), cytomegalovirus (CMV), hepatitis C virus (Kooyk, and Geijtenbeek, 2004) and Dengue virus (Tassaneetrithep, 2003), for which DC-SIGN is involved in early transmission and, in some cases, in immune modulation. Bacteria such as Mycobacterium tuberculosis (Geijtenbeek et al., 2003) also take advantage of DC -SIGN for blocking maturation of infected DC and for inducing immunosuppression.
Concerning human immunodeficiency virus type 1 (HIV-1) infection, it is established that DCs are the first predominant cells to be infected (Gurney, et al., 2005; Hu, et al., 2000; Shen, et al., 2010; Wilkinson and Cunningham, 2006). They greatly contribute to early-stage HIV dissemination and transmission by their ability to capture and transport virions and infect new target cells (Geijtenbeek, et al., 2000; Piguet and Steinman, 2007; Wu and KewalRamani, 2006). Trans-infections mediated by DCs can occur by distinct pathways but the most important mechanism is mediated by DC-SIGN. Due to the high binding affinity of DC-SIGN for HIV-1 envelope glycoprotein gp120, HIV-1 virions are captured by DC-SIGN expressed on DC. Captured HIV-1 virions do not undergo lysosomal degradation and thus remain infectious. Subsequently, after their migration into lymph nodes, DCs induce trans-infection of target CD4+ cells by captured HIV-1 virions, through cell-cell junctions called infectious synapses (Wu and KewalRamani, 2006). According to recent data, the vast majority of virions transmitted in trans originate from the cell plasma membrane rather than from intracellular vesicles (Cavrois, et al., 2007).
Because of the crucial role that DC-SIGN may play in the early stage of viral infections, several studies were carried out to identify synthetic DC-SIGN ligands to be used in human therapy, in particular for preventing or treating viral infections such as HIV -1 infection.
Frison et al. (2003) described that glycoclusters made of oligolysine substituted by one to four mannobiose moieties failed to bind DC-SIGN and were not internalized by DC -SIGN-expressing HeLa cells, contrary to Man-BSA (i.e., bovine serum albumin bearing 25 ±3 mannose residues) and to oligoclusters substituted by Lewis oligosaccharides.
Since the interaction of DC-SIGN with pathogen glycoproteins displaying high -mannose structures is multivalent, it was suggested that a multivalent presentation of mannosyl oligosaccharides on an adequate scaffold mimicking natural mannose structures occurring in pathogen glycoproteins was required to bind DC-SIGN (Tabarani et al., 2006, FEBS Lett., 2006, 580, 2402-2408). Accordingly, several recent studies have reported the synthesis of multivalent mannose-containing molecules. Mannose hyperbranched dendritic polymers were found to interfere with the binding between recombinant DC-SIGN and gp120 proteins (Tabarani, et al., 2006; Wang, et al., 2008). Gold mannoglyco-nanoparticles inhibited HIV trans-infection mediated by Raji-DC-SIGN cells (Martinez-Avila, et al., 2009). However, their use as an anti-HIV agent in vivo cannot be contemplated because of their toxicity. Finally, mannosyl glycodendritic structures based on second and third generations of Boltorn hyperbranched dendritic polymers functionalized with mannose inhibited HIV trans-infection mediated by THP-1/DC-SIGN cells (Sattin, et al., 2010). However, despite a good activity, such compounds display several drawbacks: they are difficult and expensive to prepare and may display a low solubility in biological media.
There is still a need for new compounds displaying a high affinity for DC-SIGN, which may be used as anti-infectious agents for the prevention and the treatment of infectious diseases such as HIV infection.